Mechanisms of Action of Second-Line Agents and Choice of Drugs in Combination Therapy
Total Page：16
File Type：pdf, Size：1020Kb
Mechanisms of action of second-line agents and choice of drugs in combination therapy E. Choy, G. Panayi Department of Rheumatology, Division ABSTRACT stimulation of IL-2 receptor (IL-2R) of Medicine, GKT School of Medicine, Second-line agents are used commonly positive lymphocytes and monocytes. King’s College, London. for the treatment of rheumatoid arthritis The latter release monokines, including Dr. Ernest Choy, MD, MRCP, Consultant (RA). They suppress inflammation and IL-1, IL-6, and tumour necrosis factor a and Senior Lecturer in Rheumatology; ameliorate symptoms but often fail to (TNFa ) that stimulate mesenchymal Professor Gabriel Panayi, MD, DSc, substantially improve long-term disease cells such as fibroblasts, as well as en- FRCP, Arthritis Research Campaign outcome. Their use in RA was discov- dothelial cells. Activated fibroblasts, mo- Professor of Rheumatology. ered serendipitously and their modes of nocytes, and macrophages release ma- Please address correspondence and action were largely unknown. Recent re- trix metalloproteinases, such as collagen- reprint requests to: Dr. E. Choy, searches have identified some of their ases and stromelysin, that degrade con- Department of Rheumatology, GKT mechanisms of action. Most of them have nective tissues and result in tissue dam- School of Medicine, King’s College antiinflammatory properties and some age. Stimulated endothelial cells up-re- Hospital (Dulwich), East Dulwich are immunomodulators. Traditionally, gulate surface vascular adhesion mole- Grove, London SE22 8PT, U.K. second-line agents are used as mono- cule expression. These include selectins Clin Exp Rheumatol 1999; 17 (Suppl. 18): therapy, but recent evidence suggests and integrins such as intercellular adhe- S20 - S28. that combination treatment with two or sion molecule 1 (ICAM-1) and vascular © Copyright CLINICAL AND more drugs may be more efficacious. cell adhesion molecule 1 (VCAM-1). EXPERIMENTAL RHEUMATOLOGY 1999. However, the choice of agents in combi- This leads to increased recruitment of nation therapy is not based on their leukocytes into the inflammatory site and Part of this article has been previously published in “How do second- line agents mechanisms of action. We review current augments the immune response. work ?” by E.H.S. Choy and G.H. Kingsley, knowledge on the modes of action of sec- The release of chemokines such as IL-8 in Immunology of Rheumatoid Disease, ond-line agents and assess whether such further augments leucocyte trafficking edited by J. Saklatvala and M.J. Walport, understanding may offer a rational ba- into the inflamed joint. IL-6 stimulates Edinburgh, Churchill Livingstone, sis for combination therapy. hepatocytes to release acute phase reac- 1995; 51 (2): 472-492. tants and is the main cytokine responsi- Introduction ble for the raised erythrocyte sedimen- Key words: Second-line or disease-modifying anti- tation rate (ESR) and C-reactive protein Rheumatoid arthritis, treatment, rheumatic drugs (DMARDs) are stand- (CRP) in RA. Within this inflammatory combination, DMARD. ard treatment for rheumatoid arthritis milieu, there are factors, such as trans- (RA). Some, but not all, DMARDs re- forming growth factor b (TGFb) and IL- tard joint damage (1). For all the current 10, which down-regulate inflammation. DMARDs, their use in RA has come The degree of inflammation in RA rests about through serendipity rather than on the balance between the pro-inflam- rational development. This, unfortunate- matory and antiinflammatory mediators. ly, reflects our ignorance of the precise The exact role of B cells in the patho- etiopathogenesis of RA. The exact mech- genesis of RA is unclear, but the pres- anism of action of most DMARDs re- ence of rheumatoid factor (RF) and hy- mains unknown. pergammaglobulinemia in RA patients Recent researches have increased our suggests that they may have a role in the understanding of inflammation and path- inflammatory process. A high titre of RF ogenesis of RA. This has been reviewed is associated especially with a poor prog- extensively elsewhere (2, 3). Briefly, RA nosis, erosive disease, and extra-articu- is thought to be driven by unknown anti- lar manifestations. genic peptides presented in the groove Clinical trials of DMARDs have con- of human leucocyte antigen (HLA)-DR firmed their ability to reduce joint pain, molecules to CD4+ T lymphocytes. swelling, and early morning stiffness, all These antigen-specific CD4+ T cells re- of which are features of inflammation. lease lymphokines such as interleukin-2 Hence, most research efforts have fo- (IL-2) and interferon-g (IFNg) to activate cused on the effects of DMARDs on the inflammatory cascade through the various inflammatory mediators. In or- S-20 Hypothalamus-pituitary-adrenocortical and -gonadal axis in RA / M.Mechanisms Cutolo of action of second-line agents / E. ChoyEDITORIAL & G. Panayi der to elucidate the mechanism by which tion in the number of monocytes (8). Preincubating monocyte or B cell enrich- a particular DMARD acts in RA, it is Furthermore, in vitro aurothiomalate is ed PBMNC with aurothiomalate inhib- vital to obtain both in vivo and in vitro a potent inhibitor of peripheral blood ited the mitogen stimulated production evidence. On its own, the former may mononuclear cell proliferation induced of immunoglobulin in vitro (18). This is reflect merely disease improvement or by mitogen, antigen, or mixed allogeneic confirmed by in vivo and ex vivo data other factors rather than a direct action lymphocytes (9-12). This is, at least in showing that chrysotherapy reduces im- of the second-line drug. The results of part, a direct effect on monocytes, since munogobulin, immune complexes, and in vitro studies vary greatly with the ex- addition of untreated monocytes could RF levels in serum (19, 20). Further- perimental model used, which may not reverse the inhibition (10). Although more, the side effects of gold include hy- truly reflect the complex in vivo situa- such monocytes showed the decreased pogammaglobulinemia and selective IgE tion. Furthermore, any in vitro effect expression of major histocompatibility and IgA deficiency (21). must be demonstrable at doses that complex (MHC) class II molecules, this The effect of gold compounds on cyto- would be achieved in patients. This may may not be the mechanism of action in kine expression remains unclear. In vivo be difficult to determine for some prepa- vivo since a high dose of aurothiomalate Madhok et al. found that after chryso- rations. These caveats should be borne was required in vitro to produce such therapy there was a reduction in serum in mind in assessing many apparent con- effects (10). IL-6 which was correlated with disease flicts in the current literature. Although aurothiomalate inhibits mito- activity, but this may be due to disease gen-stimulated peripheral blood mono- improvement rather than a direct effect Gold nuclear cell (PBMNC) proliferation and of gold (22). Farahat et al. studied se- On the assumption that RA was caused expression of IL-2 and IL-2R, hitherto quential synovial biopsies and showed by mycobacterial infection, Forestier et there is no convincing direct evidence that there was a significant decrease in al. treated the first RA patient with gold to suggest that aurothiomalate exerts its the expression of IL-1a , IL-1b, IL-6, and in 1929 (4). The clinical efficacy of gold prime therapeutic effect through a direct TNFa after 12 weeks of chrysotherapy in RA was demonstrated by a multicen- action on lymphocytes (12). Interest- (8). In vitro, Harth et al. found that auro- tre trial in the UK published in 1960 (5). ingly, Verwilghen et al. showed that lym- thiomalate inhibited the production of Gold salts are administered either orally phocytes from patients who developed IFNg from concanavalin A-stimulated as auranofin or intramuscularly as sodi- gold-induced skin rashes proliferated peripheral blood mononuclear cells both um aurothiomalate in the UK, and as so- specifically to gold (13). Surprisingly, in RA patients and normal controls (23). dium aurothioglucose in some European this response was directed against gold Danis et al. showed that aurothiomalate countries. Whilst intramuscular gold (III) rather than gold (I), which is the had a bimodal effect on IL-1 production compounds appear to have similar mech- form actually found in aurothiomalate by lipopolysaccharide-stimulated mono- anisms of action and pharmacokinetics, (13). It was therefore postulated that gold cytes (24). At low concentrations, the it is unclear to what extent auranofin was oxidized from gold (I) to gold (III) production of IL-1 was enhanced, while shares these characteristics. in vivo, perhaps in the phagolysosomes higher concentrations had the opposite The primary therapeutic effect of gold of monocytes, macrophages, and neutro- effect. These changes in cytokines could, salts appears to be on polymorphonu- phils. Of particular interest, the patients of course, be secondary to the effect of clear cells (PMN), monocytes, and en- who developed skin rashes as a result of aurothiomalate on monocytes. However, dothelial cells, though they may also af- chrysotherapy tended to be those who one intriguing mode of action of gold fect B cells and cytokines. responded particularly well to treatment may be the direct inhibition of DNA In vitro aurothiomalate and auranofin at (14), suggesting that the induction of this binding by transcription factors (TF) pharmacologic doses inhibit PMN pha- gold (III)-specific T cell response might (25). TF such as activator protein 1 (AP- gocytosis, aggregation, chemilumines- also be linked to a therapeutic mode of 1) and, to a lesser extent, AP-2, nuclear cence, and the generation of superoxide action of aurothiomalate. factor 1 (NF-1), and TFIID are involved (6). Interestingly, auranofin is a more Gold is known to affect endothelial cell in the production of cytokines and have potent inhibitor than aurothiomalate in proliferation and HLA expression (15). been shown to be inhibited in vitro by these systems, whilst the latter is more It has also been shown to affect leucocyte gold (25).